Arnold Hilgers Institute
Chris De Bruijn and Arnold Hilgers
European Institute of Molecular Medicine (EURIMM)
Chronic diseases, including mental depression and chronic fatigue, are invariably associated with a chronically unbalanced immune system. Restoration of proper immune function with natural substances, elimination of triggering factors, combined with genotypic and phenotypic analysis, represents a novel, highly promising approach for individualised treatment and prevention of these conditions.
Chronic diseases are of multifactorial origin with genotype, immune system, environment and life-style playing a role in development and course of the disease. All these factors can lead to a dysregulation of the interplay between brain and immune system (hypothalamic-pituitary-adrenal axis) (1,2). As a result of the work of Hilgers and his group in Düsseldorf, a series of studies has been published providing evidence for the coexistence of mental depression, chronic immune stimulation and inflammatory reaction patterns in a vast range of chronic diseases (3,4,5). It was further shown, that a number of environmental factors are intimately involved in the development of chronic immune stimulation and imbalances in the activities of immune cells (6). In genetically predisposed individuals Hilgers et al. found nutrition- and life style-induced immune imbalances associated with symptoms of mental depression (6,7). Using specific combinations of nutrients (e.g. antioxidants, amino acids, minerals, omega-3 polyunsaturated fatty acids), immunity inducers and immunoglobulins it was possible to restore the immune function and improve mental health (4,5). These studies paved the way for understanding the role of the “brain/immune connection” which in chronic diseases at the same time can affect body and mind.
The brain, with its connections to the neuroendocrine system (e.g. specific brain areas, such as the hypothalamus and the pituitary; the adrenals etc.) and the immune system form one integral, body-wide operating coordinative network (8- 11). By responding to changes in the daily environment (infections, stress, nutrition etc.), this network continuously modulates the activity of genes, maintains the balance between all body functions (homeostasis) and, if necessary, acts to re-adjust homeostasis to the equilibrium that is needed for healthy survival of the individual (12,13).
Both the brain and the immune system produce signal substances (neuropeptides and cytokines, respectively) that can be “read” by both immune cells and cells from the central nervous system: everywhere in the PNI-network (“immune system / brain network“) the same language is spoken (14-17).
The so-called “cytokine network“ is responsible for the bi-directional exchange of information between the brain and the immune system. A major role in the regulation of this cytokine network is played by the T-helper (Th) lymphocytes, in cooperation with other types of white blood cells, such as T-suppressor cells, macrophages and natural killer cells. This has extensively been documented in individuals with acute and chronic stress, major depression, chronic inflammation and chronic infection (18-25).
Cytokines were initially discovered in the immune system as mediators of communication between various types of immune cells. However, genes encoding various cytokines are also expressed in vascular and neuronal structures of the adult brain and adrenal gland, supporting evidence for a role of cytokines as modulators of CNS function and behaviour (26-29).
Th cells may be functionally defined by their cytokine profiles. Cells participating in a Type 1 (Th1-like) response typically produce Interleukin-1 (IL-1), IL-2, Interferon-γ and Tumour Necrosis Factor-α (TNF-α). Type 1 cytokines classically participate in cellular immune responses against intracellular pathogens, such as viruses and some bacteria. Cells participating in a Type 2 (Th2-like) response produce IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13. Type 2 cytokines classically regulate humoral immune responses against extra cellular infections, such as multi-cellular parasitic organisms (30,31).
Changes affecting one part of the PNI-network network (e.g. disturbance of immune balances in chronic immune stimulation) have always consequences for the other part (e.g. by causing alterations in brain functions) (29,32,33). Also the opposite is true: events in the brain (e.g. changed neuropeptide activity during mental stress) have a profound impact on the balances between the immune cells that produce inflammatory cytokines (e.g. T helper-1 and T helper-2 lymphocytes) (23, 34).
The interplay between brain and immune system takes place via the hypothalamic-pituitary-adrenal axis (HPA-axis): on the molecular level, acute stress causes an increased release of glucocorticoids from the adrenals and these hormones, in turn, influence the expression of cytokine genes (11,12,13). When this happens in a chronic way, the balances between the various cytokine producing immune cells are deregulated and the normal response to stress (so-called anti-inflammatory response) may turn into a state of chronic immune stimulation (pro-inflammatory reaction). This has considerable consequences for the way the immune system handles infectious agents, nutrients, environmental chemical substances, autoimmune antigens etc. (16,35,36).
Conversely, cytokines from the periphery (e.g. in case of an inflammation or infection) can influence the central nervous system through multiple routes, resulting in stimulation of the HPA-axis and up-regulation of the expression of the neuropeptide corticotropin releasing hormone (CRH) in the hypothalamus and of adrenocorticotropic hormone (ACTH) in the pituitary, with subsequent changes in the mental condition and up-regulation of glucocorticoids in the adrenals, which ultimately down regulates the immune response (37,38,39).
Under normal conditions, low (physiological) levels of cytokines allow the maintenance of neuronal reactivity and flexibility in the adult brain. But excessive and sustained production of pro-inflammatory cytokines is likely to impair both neuronal and non-neuronal cell functions, for instance by provoking apoptosis (natural cell death). Therefore, it is not surprising, that abnormal cytokine levels in the central nervous system are associated with several human diseases, including major depression and Alzheimer’s disease (40-44).
In human neurological disease states, such as multiple sclerosis and the neurodegeneration associated with the acquired immune deficiency syndrome, several inflammatory cytokines have been proposed as neuropathogenic mediators (45,46,47). In Alzheimer’s disease, there is both clinical and experimental evidence to suggest that inflammatory processes in the brain, caused in particular by TNF-α, together with the subsequent rise in free radicals, are instrumental in causing the pathological changes that underlie the disease (39,48). This view is supported by the finding that non-steroidal anti-inflammatory drugs (NSAID's) slow down the progression of the disease (49).
It is interesting to note, that these NSAID’s are antioxidants and that also other antioxidants (e.g., vitamin E, ginkgolides derived from Ginkgo biloba extracts) have been shown to exhibit similar activity (50,51). All these compounds have in common, that they suppress the cytokine-induced expression of cyclooxygenase II (COX-II) and inducible nitrogen monoxide syntheses (iNOS) via inhibition of the Nuclear Factor kappa-Bèta (NFκB) system in the cell nucleus (52,53,54).
This “master gene” controls inflammatory and apoptotic pathways and its expression is regulated by the redox status of the cell (balance between oxidants and antioxidants). This has extensively been documented both in animal and human studies, after administration of nutritional anti-oxidative substances (e.g. certain vitamins, bioflavonoids and other natural phenolic, plant-derived compounds) (55,56).
Immune balance and mental depression are considered as factors that mutually influence each other. Therefore, depression is receiving more and more attention as a signal of an impairment of the immune system / brain network and can be interpreted as an indication of a chronically disturbed homeostasis. In other words: depression might be considered as a pro-syndrome of chronic degenerative disease. In what clinical form such a chronic degenerative disease will become expressed, seems to be dependent on individual genetic and on environmental factors.
Many studies in humans have demonstrated the influence of mental stress on the susceptibility to infections (including HIV, Chlamydia and CMV infection) and on survival in malignant diseases (57,58). In autoimmune diseases, a high prevalence of depression, as well as a particular sensitivity to stressful events, seem to modify the course of conditions, such as in systemic lupus erythematodes, rheumatoid arthritis or Sjögrens´s disease (33,59). As a rule, a better condition of the immune parameters is associated with a better clinical course.
Conversely, there is evidence to suggest that impairment of immune function, such as during chronic infection, cancer and autoimmune disorders, is associated with the development of behavioural symptoms similar to those seen in the context of chronic stress or major depression (33).
Nutritional compounds are known to have a considerable impact on the Th1 / Th2 immune balance. On one hand this concerns anti-oxidative nutrients, such as vitamins, phenolic plant metabolites (including bioflavonoids), omega-3 fatty acids and certain minerals, such as selenium (56,60,61,62). These nutrients are known to downregulate the expression of pro- inflammatory cytokines and related substances by their interaction with the NFĸB system.
Certain nutritional antigens (such as milk proteins and plant-derived glycoproteins) impair the physiological Th1 / Th2 balance, resulting in impaired overall Th-cell functions (63,64). This may lead to certain forms of food intolerance, including Type 3 and Type 4 hypersensitivity in genetically predisposed individuals. Such a situation may also occur in association with a chronically stimulated immune system (e.g. in the case of a persistent microbial infection) (3,5).
A number of dietary components, such as omega-3-polyunsaturated fatty acids (omega-3-PUFA´s) from fish oil, have anti-inflammatory activities: they can down regulate the expression of type 1 cytokines, such as TNFα and IL-1 and of mediators of inflammation, such as COX II, iNOS and pro-inflammatory prostaglandins, such as PGE2 (60,61). In contrast, other fatty acids (saturated animal fats, hydrogenated plant oils, excess omega-6-polyunsaturated fatty acids, such as linoleic acid) can have pro-inflammatory effects (65,66).
In psychiatric patients it has been shown that omega-3 PUFA's have significant positive effects on the mental status (67,68). Others have shown, that this is also the case in major depression and that this effect was accompanied with an improvement of the immune balance (Maes et al., 2003, personal communi-cation). Therefore, metabolic profiles, providing a detailed analysis of the lipid- and fatty acid status, are considered to be essential for a comprehensive evaluation of the function of the immune system / brain network and therefore they are part of the proposed project plan
Since 1991 our group has published a series of studies providing evidence for the co-existence of mental depression, chronic immune stimulation and inflammatory reaction patterns in patients with a.o. chronic Chlamydia-, Cytomegalovirus- and Herpes simplex virus infections (3-6). The immunological imbalances in these patients mostly pointed to impaired functioning of certain types of immune cells (such as T helper cells, T-suppressor cells, macrophages, natural killer cells). Earlier, in 1986, one of us (A.H.) has been the first European investigator to publish on the immunological aspects of chronic fatigue and to coin the name “chronic fatigue immune dysfunction syndrome”.
A whole range of immunological abnormalities (disturbed balances between the activities of the various immune cells) have consistently been observed in patients with chronic fatigue syndrome and fibromyalgia. A specific type of immune cells, the macrophages, was found to play a decisive role in the manipulation of the immune balance in these patients (3-5). This not surprising, since macrophages are known to be the “hiding” place for many organisms that cause chronic infections. In the case of chronic Chlamydia infections, it was recently shown by others, that chlamydial cells, surviving inside macrophages, produce specific peptides that impair the function of other immune cells (T-helper cells) and, eventually, cause the death (apoptosis) of these T-helper cells (69). On the other hand, Chlamydia inhibits the cell death (apoptosis) of human macrophages by induction of IL-10, a supporter of macrophage growth (70), thereby supporting the mechanism of persistent infection.
In genetically predisposed individuals, we have found nutrition- and lifestyle-induced immune imbalances (e.g. Type 3 and Type 4 hypersensitivity reactions, autoimmune pathology, pulmonary diseases) to be associated with specific dietary proteins (notably from milk, wheat, rye, yeast, fish and chicken), heavy metals (notably lead, mercury and cadmium), ingredients of industrially prepared food products, including fast food (e.g. glutamate; various preserving agents and thickeners; ready-to-use meals, fast food products), and smoke (smoked food, cigarettes) (3,4,5). Practically always symptoms of vital exhaustion and mental depression were encountered in these patients.
An often forgotten category of diseases with chronically disarranged immune functions is related to the use of pharmaceutical drugs: ca. 30% of the adverse reactions of medicaments can be traced down to the detrimental effects of therapeutic chemicals on the immune system, especially in genetically predisposed persons. It was found by us and by others, that the individual reactivity towards drugs does not only cause so-called direct-type allergies (asthma, skin rash, eczema as a reaction to aspirin, antibiotics, or contrast media), but even more frequently of so- called direct-type allergies (asthma, skin rash, eczema as a reaction to aspirin, antibiotics, or contrast media), but even more frequently of so-called delayed type allergic reactions, that may even lead to autoimmune symptoms (such as reactions to anti-depressants, pain killers, anti-rheumatic medications, estrogens, and androgens) (4,5). The immunological effects of cancer treatments (chemotherapy, radiation therapy, surgical stress) are widely known as well.
Using specific combinations of nutrients (antioxidants, amino acids, minerals, polyunsaturated fatty acids), unspecific immunity inducers and immunoglobulins, we have been able to restore immune function (notably the Th1 / Th2 cytokine balance) in a significant number of patients with chronic diseases accompanied with mental disorders (4,5). In several cases associated with infectious agents, the treatment has also successfully been combined with conventional antibiosis (5).
Recent research shows that most genes are present in variant forms in the human population. These variants have very small structural differences, for instance just one single nucleotide out of the several thousand nucleotides that form a gene. Such variant forms (single nucleotide polymorphisms; SNP's) give rise to a protein with a slightly different structure. This variant protein may work satisfactorily under most normal conditions, but when it comes under “pressure” (e.g. in case of a chronic infection or during the metabolism of certain food components, pharmaceutical drugs or drugs of abuse), it might perform less adequately and cause an imbalance in the regulating mechanisms of the major “maintaining system” of the body. If not brought back to balance properly in due time, this may ultimately lead to disease.
There is substantial evidence, that naturally occurring forms of such variant genes, so-called single nucleotide polymorphisms (SNP’s or “Snips”) confer individual susceptibility to the development of a certain disease-prone phenotype (for instance, gene variants that are associated with a lowered anti-oxidative capacity, leading to a decreased resistance in cases of oxidative stress and accelerated aging processes), even though there is only a minimally altered function of the variant gene products. This means, that genetically predisposed persons may age more rapidly and develop more easily a chronic degenerative disease than other persons (71). Every human being carries a number of such variant genes and this explains, why even identical external factors can nevertheless cause different reactions in different people.
Based on the emerging evidence that SNP analysis can have considerable predictive value, we have started using predictive genomic screening in the context of the treatment and prevention of chronic disease.
Requirements for SNP’s to be used for this purpose include:
When these requirements are fulfilled, predictive genomic testing will provide improved healthcare for all patients, but especially for
Since the immune system and the nervous system function as one functional unit, a chronic immune imbalance is mostly also associated with a mental imbalance. This explains why in a chronic disease there is always a chronically unbalanced PNI-network and why in such diseases mental disorders play such a prominent role. This has been shown in detail in major depression, chronic fatigue syndrome, autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis), cardiovascular diseases and malignant diseases. It has been shown, that restoration of the proper immune balances not only offers novel effective therapeutic, but also novel preventive options for these conditions.
As has been stated above, the form in which a chronically unbalanced PNI-network leads to a chronic disease, can vary considerably from individual to individual: this depends on the individual genetic predisposition and on personal environmental and life style factors. Consequently, a new approach that integrates these factors will be more successful than the mono-disciplinary, organ-based concepts that are used in conventional medicine.
The new, unifying paradigm for chronic disease treatment is based on modulating the function of the “brain / immune network” (PNI-network balance).
It postulates that:
Apart from the analysis of the structure of genes (the scientific field that is called “genomics”), also the functional analysis of the actual expression of genes in the form of proteins and related cellular functions (the field of “proteomics”) is of significant importance. In the proteomics context, the PNI-network is in the focus of the “New Medicine” paradigm.
A third essential scientific field is “metabolomics”, providing information on how gene activity influences metabolic reactions, especially those regulating and coordinating the cellular activities and signalling balances within the PNI-network. Integration of the data obtained from all three areas (genomics, proteomics and metabolomics) allows for a detailed individual diagnostic fingerprint of a person and for taking rational interventional or preventive steps.
Applying this his new paradigm to clinical practise has shown that
This new paradigm forms the fundament of a “New Medicine”, which provides a subtle, tailor-made medicine and which has considerable potential not only for curing physical and mental disorders, but even more for prevention of chronic degenerative diseases.
EURIMM Workshop 05/2004
Chronic Fatigue Immune Dysfunction Syndrome (CFIDS): Ein Modell für den Paradigmenwechsel in der Diagnose und Therapie chronischer Erkrankungen, Dr. Arnold Hilgers, European Institute of Molecular Medicine (EURIMM)
EURIMM Workshop 2004:
CFIDS - A Model for a Paradigm-change in the Diagnosis and Therapy of Chronic Diseases